The present invention relates to a brain-derived neurotrophic factor being modified with a 1-acyl-glycerol derivative. In addition, the present invention also relates to an agent for treatment of type 2 diabetes mellitus, which comprises as the active ingredient a brain-derived neurotrophic factor being modified with a 1-acyl-glycerol-derivative.
One of the neurotrophic factors, a brain-derived neurotrophic factor (hereinafter, occasionally referred to as BDNF), is a protein, which is provided from target cells or neurons and glial cells and Schwann cells in the living body, and shows activities to maintain the survival and differentiation of neurons. BDNF has been known to act as a specific ligand of receptor (trkB), which is a product of p75 and trk genes (cf., Takeshi NONOMURA, Hiroshi HATANAKA; Jikken Igaku, vol. 13, p. 376 (1995)).
BDNF has been known as a therapeutic agent for treatment of neurodegenerative diseases (e.g., ALS) or diabetic peripheral neuropathy (cf., A. P. Mizisin, et al., Journal of Neuropathology and Experimental Neurology, vol.56, p. 1290 (1997)).
In addition, WO 98/32458 discloses that BDNF is useful as a therapeutic agent for treatment of diabetic mellitus.
Since BDNF is a useful protein exhibiting the above mentioned various functions, it has been desired to develop a compound with more efficacious and more excellent pharmacokinetics with retaining inherent activities of BDNF.
There has been tried to improve the physical properties and activities of proteins with maintaining their functions by modifications. For example, JP 2679852 and JP 2718809 disclose common techniques of modifying physiologically active proteins with lecithin or lysolecithin, specifically modification of superoxide dismutase (SOD). However, there is no specific disclosure of modifying BDNF, which is a useful protein exhibiting various functions.
An object of the present invention is to provide a compound being more efficacious with retaining inherent activities of BDNF and further having an excellent pharmacokinetics.
The present inventors have found that the pharmacological activities, pharmacokinetics and physical properties of BDNF are improved by modifying BDNF with a 1-acyl-glycerol derivative, and have accomplished the present invention.
More particularly, the present invention relates to the following:
(1) A BDNF being modified with a 1-acyl-glycerol derivative:
(2) A modified BDNF according to the above (1), which is the compound of the formula (1):
A(Xxe2x80x94B)m xe2x80x83xe2x80x83(1) 
wherein A is a residue of brain-derived neurotrophic factor,
B is a residue of a 1-acyl-glycerol derivative having a hydroxyl group at the 2-position of the glycerol moiety, which is prepared by removing a hydrogen atom from the hydroxyl group,
X is a chemical cross-linkage, and
m is an average number of the introduction and is not less than about 0.5;
(3) A modified BDNF according to the above (2), wherein X is a group of the formula (2): 
wherein R1 is an alkylene group,
or a group of the formula (3): 
wherein R2 and R3 are independently an alkylene group;
(4) A modified BDNF according to the above (2), wherein the 1-acyl-glycerol derivative is 1-acyl-glycero-3-phosphoryl choline, 1-acyl-glycero-3-phosphoryl serine, or 1-acyl-grycero-3-phosphoryl ethylamine;
(5) A modified BDNF according to the above (2), wherein B is a 1-acyl-glycero-3-phosphoryl choline residue of the formula (4): 
wherein R4 is an acyl group,
a 1-acyl-glycero-3-phosphoryl serine residue of the formula (5): 
wherein R4 is an acyl group,
or a 1-acyl-glycero-phosphoryl ethylamine residue of the formula (6): 
wherein R4 is an acyl group;
(6) A modified BDNF according to the above (2) or (3), wherein B is a group of the formula (4): 
wherein R4 is an acyl group;
(7) A modified BDNF according to any one of the above (2), (3), (4), (5) and (6), wherein the acyl group is an alkanoyl group having 8 to 30 carbon atoms;
(8) A modified BDNF according to any one of the above (2), (3), (4), (5), (6) and (7), wherein the acyl group is palmitoyl group;
(9) A modified BDNF according to any one of the above (2), (3), (4), (5), (6), (7) and (8), wherein m is in the range of from about 1 to about 6;
(10) A modified BDNF according to any one of the above (2), (3), (4), (5), (6), (7), (8) and (9), wherein X is a group of the formula (2): 
wherein R1 is an alkylene group;
(11) A modified BDNF according to the above (10), wherein R1 is a straight chain alkylene group having 2 to 10 carbon atoms;
(12) A modified BDNF according to the above (10), wherein R1 is trimethylene;
(13) A modified BDNF of the formula (7):
A(Xxe2x80x94B)n xe2x80x83xe2x80x83(7) 
wherein A is a residue of brain-derived neurotrophic factor,
B is a residue of a 1-acyl-glycerol derivative having a hydroxyl group at the 2-position of the glycerol moiety, which is prepared by removing a hydrogen atom from the hydroxyl group,
X is a chemical cross-linkage, and
n is an integer of 1 or more;
(14) A modified BDNF according to the above (13), wherein X is a group of the formula (2): 
wherein R1 is an alkylene group, or
or a group of the formula (3): 
wherein R2 and R3 are independently an alkylene group;
(15) A modified BDNF according to the above (13), wherein B is a 1-acyl-glycero-3-phosphoryl choline residue of the formula (4): 
wherein R4 is an acyl group,
a 1-acyl-glycero-3-phosphoryl serine residue of the formula (5): 
wherein R4 is an acyl group,
or a 1-acyl-glycero-phosphoryl ethylamine residue of the formula (6): 
wherein R4 is an acyl group;
(16) A modified BDNF according to the above (13) or (14), wherein B is a group of the formula (4): 
wherein R4 is an acyl group;
(15) A therapeutic agent for treatment of type 2 diabetes mellitus, which comprises as the active ingredient a BDNF being modified with a 1-acyl-glycerol derivative;
(16) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (15), which is a compound of the formula (1):
A (Xxe2x80x94B)m xe2x80x83xe2x80x83(1) 
wherein A is a residue of brain-derived neurotrophic factor,
B is a residue of a 1-acyl-glycerol derivative having a hydroxyl group at the 2-position of the glycerol moiety, which is prepared by removing a hydrogen atom from the hydroxyl group,
X is a chemical cross-linkage, and
m is an average number of the introduction and is not less than about 0.5;
(17) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (16), wherein X is a group of the formula (2): 
wherein R1 is an alkylene group,
or a group of the formula (3): 
wherein R2 and R3 are independently an alkylene group;
(18) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (16), wherein the 1-acyl-glycerol derivative is 1-acyl-glycero-3-phosphoryl choline, 1-acyl-glycero-3-phosphoryl serine, or 1-acyl-grycero-3-phosphoryl ethylamine;
(19) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (16), wherein B is a 1-acyl-glycero-3-phosphoryl choline residue 
wherein R4 is an acyl group,
a 1-acyl-glycero-3-phosphoryl serine residue of the formula (5): 
wherein R4 is an acyl group,
or a 1-acyl-glycero-phosphoryl ethylamine residue of the formula (6): 
wherein R4 is an acyl group;
(20) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (16) or (17), wherein B is a group of the formula (4): 
wherein R4 is an acyl group;
(21) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to any one of the above (16), (17), (18), (19) and (20), wherein the acyl group is an alkanoyl group having 8 to 30 carbon atoms;
(22) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to any one of the above (16), (17), (18), (19), (20) and (21), wherein the acyl group is palmitoyl group;
(23) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to any one of the above (16), (17), (18), (19), (20), (21) and (22), wherein m is in the range of from about 1 to about 6;
(24) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to any one of the above (16), (17), (18), (19), (20), (21), (22) and (23), wherein X is a group of the formula (2): 
wherein R1 is an alkylene group;
(25) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (24), wherein R1 is a straight chain alkylene group having 2 to 10 carbon atoms;
(26) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (25), wherein R1 is trimethylene;
(27) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF, which is the compound of the formula (7):
A(Xxe2x80x94B)n xe2x80x83xe2x80x83(7) 
wherein A is a residue of a brain-derived neurotrophic factor,
B is a residue of a 1-acyl-glycerol derivative having a hydroxyl group at the 2-position of the glycerol moiety, which is prepared by removing a hydrogen atom from the hydroxyl group,
X is a chemical cross-linkage, and
n is an integer of 1 or more;
(28) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (27), wherein X is a group of the formula (2): 
wherein R1 is an alkylene group,
or a group of the formula (3): 
wherein R2 and R3 are independently an alkylene group.
(29) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (27), wherein B is a 1-acyl-glycero-3-phosphoryl choline residue of the formula (4): 
wherein R4 is an acyl group,
a 1-acyl-glycero-3-phosphoryl serine residue of the formula (5): 
wherein R4 is an acyl group,
or a 1-acyl-glycero-phosphoryl ethylamine residue of the formula (6): 
wherein R4 is an acyl group;
(30) A therapeutic agent for treatment of type 2 diabetes mellitus comprising as the active ingredient a modified BDNF according to the above (27) or (28), wherein B is a group of the formula (4): 
wherein R4 is an acyl group.